Cholecystokinin (CCK) is a neuropeptide with a widespread distribution in brain. CCK receptors are classified into two types; CCK.sub.A and CCK.sub.B, both of which are present in brain (Woodruff, G. N. and Hughes, J., 1991, Ann. Rev. Pharmacol. 31, 469-501).
Devazepide is a selective antagonist of CCK.sub.A receptors. The chemical name and structure of devazepide are:
1H-indole-2-carboxamide, N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-, or (L 364718) and ##STR1##
L-365,260 is a selective antagonist of CCK.sub.B receptors. The chemical name and structure of L-365,260 is (R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-methylphenyl)urea and ##STR2##
Other CCK antagonists are lorglumide and loxiglumide. Lorglumide is DL-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxopentanoic acid and loxiglumide is (.+-.)-4-[(3,4-dichlorobenzoyl)amino]-5-[(3-methoxyproxyl)pentylamino]-5-o xo-pentanoic acid.
These CCK.sub.A and CCK.sub.B antagonists are described in U.S. Pat. No. 4,791,215 and U.S. Pat. No. 4,820,834. These documents are hereby incorporated by reference.
The above patents cover compounds of the instant invention, methods for preparing them, and several uses thereof.
The uses disclosed are gastric acid secretion disorders, gastrointestinal motility, pancreatic secretions, dopaminergic functions, analgesics, psychic disturbances, anorexia, weight increases in farm animals, and pathological cellular growth such as tumors.
Other CCK antagonists include compounds (J. Med. Chem. 1991, 34, 1505-8) of formula ##STR3## or a pharmaceutically acceptable salt thereof wherein
X.sub.o is hydrogen, fluorine, chlorine, methoxy, or trifluoromethyl;
X.sub.m is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, propoxy, trifluoromethyl, cyclopentyloxy, MeS, or NMe.sub.2 ;
X.sub.P is hydrogen, fluorine, chlorine, bromine, methoxy, or X.sub.m and X.sub.p together form --OCH.sub.2 O--;
Y is hydrogen, fluorine, bromine, chlorine, or methoxy; and
R is hydrogen or methyl.
These CCK-B receptor ligands are also useful as agents in the treatment of depression.
Other compounds (presented at the 23rd Central 24th Great Lakes Joint Regional American Chemical Society Meeting; Abstract No. 306) useful in treating depression are those of formula ##STR4## or a pharmaceutically acceptable salt thereof,
wherein R is 2,3-dichloro, hydrogen, 4-trifluoromethyl, 4-chloro, 4-bromo, 4-methyl, 4-ethyl, 4-isopropyl, 4-methoxy, 4-OCH.sub.2 Ph, 3-trifluoromethyl, 3-methyl, 3-methoxy, 3-trifluoromethyl, 4-chloro, 3,4-dichloro, 3,4-(CH.sub.2).sub.3, 3,4-(CH.sub.2).sub.4, 2-trifluoromethyl;
R.sub.2 is hydrogen or methyl; and
R.sub.3 is hydrogen or methyl.
Other compounds useful for treating depression are those of formula ##STR5## or a pharmaceutically acceptable salt thereof wherein R.sup.4 is 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 3-quinolinyl, 6-quinolinyl, n-Bu, c-hexyl, CH.sub.2 Ph, CH.sub.2 Ph-3,4-diCl, (CH.sub.2).sub.2 Ph, (CH.sub.2).sub.2 Ph-2-Cl, or (CH.sub.2).sub.3 Ph.
Other compounds useful for treating depression are those of formula ##STR6## or a pharmaceutically acceptable salt thereof wherein
R.sup.1 is 4-trifluoromethyl or 4-bromo;
R.sup.2 is hydrogen, 2-chloro, 3-cyano, 3-methoxy, 4-N(Me).sub.2, 2-methoxy, 2,3-dichloro, 3-CONH.sub.2, 4-NO.sub.2 ;
R.sup.3 is hydrogen, 2-chloro, 3-chloro, 4-chloro, 3-methoxy, or 4-methoxy.
Especially useful are compounds of formula IV wherein R.sup.1 is 4-CF.sub.3, R.sup.2 is 2-Cl, and R.sup.3 is hydrogen and wherein R.sup.1 is 4-Br, R.sup.2 is 2-Cl, and R.sup.3 is 2-Cl.
Other compounds useful in treating depression are those of formula ##STR7## or a pharmaceutically acceptable salt thereof wherein
R.sup.1 is 4-bromo or 4-trifluoromethyl;
R.sup.2 is phenyl, 3-pyridyl, or n-butyl; and
R.sup.3 is 1-naphthyl, phenyl, or n-butyl.
Other compounds useful in treating depression are those of formula ##STR8## or a pharmaceutically acceptable salt thereof wherein
X is absent, CH.sub.2, oxygen, or sulfur, and R is trifluoromethyl, bromine, or chlorine.
Other compound useful are selected from: ##STR9## or a pharmaceutically acceptable salt thereof.
Especially useful as agents for depression are CCK antagonists
1-pyrazolidinecarboxamide, N-(4-bromophenyl)-3-oxo-4,5-diphenyl-, trans-,
1-pyrazolidinecarboxamide, 5-(2-chlorophenyl)-3-oxo-4-phenyl-N-[4-trifluoromethyl)phenyl]-, trans-, and
1-pyrazolidinecarboxamide, N-(4-bromophenyl)-5-(2-chlorophenyl)-3-oxo-4-phenyl-, trans-.
The above references do not disclose the use of CCK antagonists for treating depression.
Depression can be the result of organic disease, secondary to stress associated with personal loss, or idiopathic in origin. There is a strong tendency for familial occurrence of some forms of depression suggesting a mechanistic cause for at least some forms of depression. The diagnosis of depression is made primarily by quantification of alterations in patients' mood. These evaluations of mood are generally performed by a physician or quantified by a neuropsychologist using validated rating scales such as the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. Numerous other scales have been developed to quantify and measure the degree of mood alterations in patients with depression, such as insomnia, difficulty with concentration, lack of energy, feelings of worthlessness, and guilt. The standards for diagnosis of depression as well as all psychiatric diagnoses are collected in the diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) referred to as the DSM-III-R manual published by the American Psychiatric Association, 1987.
The compounds of the instant invention have an antidepressant action in patients with major and minor forms of depression.